Hybrid Imaging of Angiogenesis and Arteriogenesis

描述(申请人提供)：外周动脉疾病(PAD)是困扰800万至1200万美国人的主要临床问题，并导致显著的死亡和残疾。有针对性的药物或基因治疗可能通过改善现有侧支动脉的血管重建(动脉生成)和/或通过刺激增加的微血管密度(血管生成)来改善这些患者的临床状况。这些生物学过程之间存在着重要的相互关系，然而，目前还不确定血管生成还是动脉生成是生理改善的主要中介。我们将描述这些过程的相互作用，特别是确定avb3整合素和一氧化氮(NO)在介导缺氧诱导的血管形成和血流诱导的动脉形成中的作用，使用已建立的小鼠后肢缺血模型。目前的提案是一个项目的竞争性更新，该项目以前旨在开发基于放射性示踪剂的非侵入性成像策略，以识别血管生成的低氧刺激，并使用针对avb3整合素的放射性示踪剂直接评估血管生成。本项目的一个主要目标是应用和改进这些方法，使用无创的混合MicroSPECT/X-射线CT成像策略，在体内评估血管生成和动脉生成在PAD中相互依赖的作用，并探索NO在调节介导这些过程的细胞上表达的整合素中的作用。我们假设，缺血可能通过调节几种细胞类型上的整合素来介导血管生成过程，由此导致的组织灌注量的增加和血管阻力的减少导致了血流介导的动脉生成的增加。该项目将利用已建立的有选择性地与avb3整合素结合的靶向放射性示踪剂，以及将跟踪与血管生成和动脉生成相关的组织灌注和缺氧的生理变化的放射性示踪剂。这种混合的MicroSPECT/CT成像系统不仅允许生物图像与正在形成的血管结构的共同配准，而且有助于示踪剂摄取的量化。目前的应用直接建立在先前开发的新的成像方法的基础上，并将利用已建立的缺血和血流诱导的血管生成模型来研究血管生成和动脉生成的关键机制，这对PAD患者的评估和管理具有潜在的重要临床意义。

DESCRIPTION (provided by applicant): Peripheral arterial disease (PAD) is a major clinical problem afflicting 8-12 million Americans, and causes significant mortality and disability. Targeted medical or genetic therapies might provide clinical improvement of these patients through improved perfusion via vascular remodeling of existing collateral arteries (arteriogenesis) and/or by stimulating increased microvascular density (angiogenesis). There is an important interrelationship between these biological processes, however, it remains uncertain whether angiogenesis or arteriogenesis is the principal mediator of physiological improvement. We will characterize the interplay of these processes, in particular defining the role of avb3 integrins and nitric oxide (NO) in mediating hypoxia- induced angiogenesis and flow-induced arteriogenesis using well established murine models of hindlimb ischemia. The current proposal is a competitive renewal of a project previously directed at development of non-invasive radiotracer-based imaging strategies for identification of the hypoxic stimulus for angiogenesis, and direct evaluation of angiogenesis using radiotracers targeted at the avb3 integrin. A principal goal of the current project is to apply and refine these methodologies using non-invasive hybrid microSPECT/X-ray CT imaging strategies for the in vivo evaluation of the interdependent roles of angiogenesis and arteriogenesis in PAD, and to explore the role of NO in the regulation of integrins expressed on cells that mediate these processes. We hypothesize that ischemia may mediate the angiogenic process through regulation of integrins on several cell types, and that the resulting increases in tissue perfusion and decreases in vascular resistance result in increased flow-mediated arteriogenesis. The project will take advantage of established targeted radiotracers that selectively bind to the avb3 integrin, along with radiotracers that will track physiological changes in tissue perfusion and hypoxia associated with angiogenesis and arteriogenesis. The hybrid microSPECT/CT imaging system not only permits co-registration of biological images with developing vascular structures but facilitates quantification of tracer uptake. The current application builds directly on the novel imaging approaches previously developed, and will take advantage of established models of ischemia- and flow-induced angiogenesis to the study a critical mechanism of angiogenesis and arteriogenesis with potentially important clinical implications for evaluation and management of patients with PAD.